A 2p12 locus with two co-regulated genes is associated to dyslexia in Finnish and German populations. H. Anthoni¹, M. Zucchelli¹, H. Matsson¹, J. Schumacher², J. Nopola-Hemmi³, H. Lyytinen⁴, G. Schulte-Körne⁵, J. Kere^1,6, M.M. Nöthen⁷, M. Peyrard-Janvid¹. 1) Dept of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden; 2) Institute of Human Genetics, University of Bonn, Germany; 3) Dept of Pediatrics, Jorvi Hospital, Finland; 4) Dept of Psychology and Child Research Center, University of Jyväskylä, Finland; 5) Dept of Child and Adolescent Psychiatry and Psychotherapy, University of Marburg, Germany; 6) Dept of Medical Genetics, University of Helsinki, Biomedicum, Finland; 7) Dept of Genomics, Life & Brain Center, University of Bonn, Germany.
   Developmental dyslexia is a common, complex disorder characterized by an unexpected difficulty in learning to read despite normal intelligence, senses and education. Genetic loci have been mapped to at least eight different chromosomes, and four candidate genes have been proposed: DYX1C1, DCDC2, KIAA0319 and ROBO1. We refined our reported 12 Mb dyslexia locus on 2p12 in 19 Finnish kindreds. TDT analysis gave significant p-values for individual markers (p=0.003) and for a four-marker haplotype (p=0.004). The results were replicated on 251 families from Germany, and an overlapping haplotype was identified (p=0.02). To further focus on the 157 kb susceptibility region, marker density was increased to one SNP every 8 kb. Two significant (p=0.005 and p=0.001) overlapping risk haplotypes covering 16 kb were identified in both populations separately and in a joint analysis. Stratification for dyslexia severity on the German sample set increased the OR for the most significant haplotype from 2.2 (p=0.006) to 5.2 (p=0.00005). We characterized thoroughly the three genes in the region, including quantification of gene expression in different parts of brain. Two neighboring genes flanking the associated haplotype were highly co-expressed in fetal and adult brains and in nine separate brain regions. Mutation screening of these two genes in the Finnish families revealed 11 coding changes, with five previously unknown and eight nonsynonymous. We conclude that the two co-regulated transcripts flanking a highly dyslexia-associated haplotype block are excellent candidates for novel dyslexia genes near the DYX3 locus.